Chapter 1

Introduction to Drug Delivery Systems

A single the most dynamic and quickly developing areas of pharmaceutical sciences is drug delivery, which includes a broad range of formulations, technologies, and tactical methods intended to effectively deliver therapeutic agents to their intended locations within the body.  The accuracy and efficiency with which the drug reaches its site of action at the right concentration and time are just as important to the efficacy of a therapeutic therapy as the intrinsic pharmacodynamic or pharmacokinetic characteristics of the active ingredient.  Even for medications with high intrinsic potency, ineffective drug delivery can result in less than ideal therapeutic outcomes, elevated systemic toxicity, and decreased patient adherence.

 The focus of contemporary pharmaceutical research has moved from simply discovering new chemical entities to creating cutting-edge drug delivery systems (DDS) that increase therapeutic efficacy, reduce side effects, and boost patient compliance.  The increasing recognition that the place, pace, and route of drug release are important factors influencing clinical outcomes has propelled this change.  Despite being popular and practical, traditional dose forms including oral tablets, capsules, and injections frequently have trouble sustaining steady plasma drug concentrations and delivering precise tissue delivery.  Advanced delivery techniques have responded by enabling regulated, prolonged, and targeted medication release. These techniques range from liposomes and nanocarriers to transdermal patches, implantable devices, and controlled-release formulations.

The creation of these advanced systems is indicative of a larger trend in precision medicine, where treatments are being tailored more and more to the requirements, genetic profiles, and illness conditions of each patient.  Modern DDS improves safety and patient quality of life by maximizing therapeutic effects while minimizing systemic exposure and adverse reactions through the optimization of drug release timing, location, and rate.

 In order to comprehend the sophisticated and cutting-edge delivery technologies covered in later chapters, this chapter offers a thorough review of the basic ideas, workings, and development of drug delivery systems.  Additionally, it emphasizes the need to develop more intelligent, patient-centered delivery strategies and the part DDS plays in providing individualized, effective, and secure medication.

Figure 1: Drug delivery system

1.1.  Fundamentals of Drug Absorption, Distribution, Metabolism, and Excretion (ADME)

The four interconnected processes of absorption, distribution, metabolism, and excretion (ADME) essentially control a drug's pharmacokinetic path through the human body.  Collectively, these phases impact a drug's bioavailability, duration of action, therapeutic efficacy, and possible toxicity, hence determining how it acts after administration.  To create the best drug delivery systems that guarantee the proper drug concentration reaches the target location at the right time and for the right amount of time, pharmaceutical scientists and physicians must have a solid understanding of ADME principles.

Ø  Absorption

Drug absorption is the process by which a medication enters the bloodstream from the site of delivery, making its way to the systemic circulation and, eventually, the site of action.  Determining the beginning, severity, and duration of a drug's therapeutic effect is an essential stage.  A drug's bioavailability, or the percentage of the administered dose that enters the systemic circulation in an active state, is directly impacted by its absorption efficiency.  Subtherapeutic effects may result from poor absorption, but toxicity may be increased by very quick absorption.  For the purpose of creating efficient medication formulations and maximizing therapeutic results, it is crucial to comprehend the variables affecting drug absorption.

Factors Affecting Drug Absorption

Drug absorption is influenced by multiple factors, which can be broadly classified into physicochemical, formulation-related, and physiological factors.

• Physicochemical Properties of Drugs: A drug's solubility, molecular size, and acid dissociation constant (pKa) all have a significant impact on how well it is absorbed.  While poorly soluble medications may have limited absorption, highly soluble pharmaceuticals are more easily absorbed in gastrointestinal fluids.  A drug's capacity to traverse lipid membranes is influenced by its ionization state, which is established by its pKa and the pH of its surroundings.  Furthermore, in general, smaller molecules disperse more readily than larger ones.
• Formulation Factors: Absorption is influenced by the drug dosage form's design as well.  Different forms, such as tablets, capsules, solutions, and others, have varying rates of medication release and absorption.  In contrast to sustained-release formulations, which are intended to release the medicine gradually over time to prolong absorption and maintain therapeutic levels, immediate-release tablets dissolve quickly in the stomach.
• Physiological Factors: The interior milieu of the body has a big influence on how well drugs are absorbed.  Absorption can be facilitated or hindered by variables such intestinal transit time, gastric pH, gastric emptying rate, and the presence of food.  High-fat meals, for instance, may improve the absorption of lipophilic medications while slowing stomach emptying.  The degree and pace of absorption can also be changed by illnesses like diarrhea or malabsorption syndromes.

1.1.1. Routes of Drug Administration

A number of routes exist for administering drugs, and each has distinct properties that affect absorption, distribution, commencement of action, and total therapeutic efficacy.  The most popular and practical approach is oral administration, which is preferred for its high patient compliance, convenience of usage, and non-invasiveness.  Drugs taken orally, however, encounter a number of physiological obstacles.  Enzymatic breakdown in the gastrointestinal tract and the stomach's acidic environment must be tolerated.  Also, the liver undergoes first-pass metabolism of many medications, which can drastically lower the amount of the active ingredient that enters the bloodstream and impact bioavailability.  Prolonged-release tablets, enteric coatings, and nanoparticles are some of the formulation techniques frequently used to get around these obstacles.

 Intravenous (IV) administration, on the other hand, gets across all absorption barriers and puts medications straight into the bloodstream.  In critical care, emergency conditions, or for medications that are poorly absorbed orally, IV administration is essential because it guarantees full bioavailability and a quick commencement of action.  Other parenteral methods offer different paths for systemic absorption, such as subcutaneous (SC) and intramuscular (IM) injections.  SC injections introduce medications into the subcutaneous fat layer for slower, longer-lasting absorption, whereas IM injections deposit medications into muscle tissue for moderate and predictable absorption.

Drugs are absorbed through the skin and gradually reach the systemic circulation when administered transdermally, providing a non-invasive method.  Although this approach is typically restricted to strong, lipophilic medications, it offers controlled and sustained release, reduces variations in plasma drug levels, and enhances patient adherence.  Additional versatility in targeting local or systemic effects is provided by other specialized routes, such as sublingual, rectal, pulmonary, nasal, and ocular administration. These routes frequently avoid first-pass metabolism and provide rapid or site-specific pharmacological action.

 The drug's physicochemical characteristics (solubility, stability, and molecular size), therapeutic goals (immediate vs. prolonged action), target site, patient state, and convenience all play a role in the route selection process.  To maximize medication therapy and guarantee both efficacy and safety, a comprehensive grasp of these pathways and their effects on absorption, bioavailability, and pharmacokinetics is necessary.

Ø  Mechanisms of Absorption

Multiple mechanisms allow drugs to get past the gut epithelium.  The most prevalent type of diffusion involves molecules moving down their concentration gradient passively, which requires no energy.  In order to help some molecules move along the concentration gradient, carrier proteins are involved in facilitated diffusion.  In order to transfer medications against their concentration gradient, active transport needs energy, which frequently enables the effective absorption of nutrients and some medications.  An uncommon method is endocytosis, in which cells ingest bigger molecules or particles into vesicles for passage across the membrane.  The physiological setting and the chemical makeup of the medicine determine each mechanism's relative contribution.

Ø  Distribution

Drug distribution is the process by which a medication spreads throughout the bodily fluids and tissues after entering the systemic circulation.  This crucial phase affects both treatment efficacy and possible toxicity by determining the drug's concentration at the target location.  The distribution pattern and extent are determined by the chemical properties of the medicine, the patient's physiology, and the qualities of different tissues.  Predicting how a drug will work, maximizing dosage, and reducing side effects all depend on a solid grasp of drug distribution.

Factors Affecting Drug Distribution

·       Several factors influence how drugs are distributed in the body:

Blood Flow to Tissues: Drugs usually reach high-blood-flow organs like the liver, kidneys, and heart more quickly than lower-perfusion tissues like cartilage or fat.  Variations in medication concentration and commencement of action across various organs can result from differences in tissue perfusion.

Protein Binding: Albumin and α1-acid glycoprotein are the two main plasma proteins that many medications bind to.  A drug's pharmacological activity and ability to pass across cell membranes are limited to its free (unbound) fraction.  Whereas displacement by other medications can raise free drug levels and toxicity risk, pharmaceuticals with strong protein binding may have limited tissue distribution and extended circulation durations.

Tissue Permeability and Partitioning: The degree of ionization, molecular size, and lipid solubility of a medicine determine its capacity to permeate tissues and bridge cell membranes.  Hydrophilic medications mostly stay in extracellular fluid, whereas lipophilic drugs tend to accumulate in fatty tissues.  Certain medications can be actively absorbed or metabolized by certain tissues, such as the liver and kidneys, which might affect their general distribution.

·       Volume of Distribution (Vd) and Its Clinical Relevance

The apparent amount of space in the body that a medicine can spread is described by the theoretical quantity known as the volume of distribution (Vd).  It is computed using the ratio of the drug's total body content to its plasma concentration.  While a low Vd implies that the medication mostly stays in the plasma, a high Vd shows wide tissue distribution.  Clinically, Vd aids in forecasting drug buildup and excretion and helps direct dosing tactics, especially for loading doses.

·       Barriers to Distribution

Drug penetration into particular tissues is restricted by certain physiological barriers.  By preventing the entry of numerous medications and big molecules, the blood-brain barrier (BBB) safeguards the central nervous system.  Preventing prenatal toxicity requires the placental barrier to control medication transfer from mother to fetus.  The ocular barrier also prevents drugs from entering the eye.  Drug design requires an understanding of these barriers in order to ensure therapeutic efficacy in target tissues and minimize unintentional exposure in sensitive areas.

Ø  Metabolism (Biotransformation)

Drug metabolism, sometimes referred to as biotransformation, is the biochemical process by which medications are chemically changed by the body, usually via enzymatic activity.  Making lipophilic (fat-soluble) medications more hydrophilic (water-soluble) so they can be more readily eliminated by the kidneys or bile is the main goal of metabolism.  In addition to aiding in the removal of pharmaceuticals, metabolism can alter pharmacological activity, occasionally turning prodrugs into their active forms or deactivating medications to stop their effects.  To anticipate drug interactions, individual response variability, and possible toxicity, it is essential to comprehend drug metabolism.

Phases of Metabolism

Drug metabolism occurs in two main phases:

• Phase I Reactions: These reactions use techniques including oxidation, reduction, and hydrolysis to add or reveal functional groups on the drug molecule.  In the liver, cytochrome P450 enzymes are the main catalysts of phase I processes.  These changes frequently make the medication somewhat more soluble in water and get it ready for Phase II conjugation.
• Phase II Reactions: Phase II metabolism, also known as conjugation reactions, entails the coupling of the medication or its Phase I metabolites with endogenous compounds such as acetate, glucuronic acid, or sulfate.  Water solubility is significantly increased by reactions like acetylation, sulfation, and glucuronidation, which aid in biliary or renal excretion.  Although active metabolites can occasionally be produced, phase II reactions often produce pharmacologically inactive metabolites.

Factors Affecting Metabolism

Drug metabolism is influenced by a number of internal and external variables.  Enzyme activity can vary greatly due to genetic polymorphisms, which might cause some medications to be metabolized quickly or slowly.  Age has an impact on metabolic capacity; old people and neonates frequently show decreased enzyme activity.  Since the majority of the enzymes that break down drugs are found in the liver, liver illness can affect metabolism and make drugs more hazardous.  Drug interactions can change the pace of metabolism and affect the effectiveness of treatment. For example, co-administered medications may induce or inhibit certain enzymes.

First-Pass Metabolism and Its Effect on Oral Drugs

First-pass metabolism, also known as presystemic metabolism, happens when medications taken orally undergo liver and intestinal wall metabolism before entering the bloodstream.  This can drastically lower some medications' bioavailability, requiring larger oral dosages or different ways to administer them in order to reach therapeutic plasma concentrations.  Designing efficient dosage schedules and anticipating inter-individual heterogeneity in medication response require an understanding of first-pass metabolism.

Ø  Excretion

The physiological mechanism via which the body gets rid of medications and their metabolites to avoid buildup and possible toxicity is called drug excretion.  It is the last phase in a medication's pharmacokinetic path and is essential for preserving suitable drug concentrations within therapeutic levels.  Effective excretion is essential in establishing the dosing interval and regimen and guarantees that the drug's action will end at the appropriate time.  To predict drug behavior in certain populations, such as those with renal or hepatic impairment, it is crucial to comprehend the mechanisms of excretion.

Major Routes of Drug Excretion

Drugs can be excreted from the body through several pathways, with the primary routes being renal and biliary.

• Renal (Urine): The most vital organs for drug removal are the kidneys.  Drugs and their metabolites undergo different levels of resorption based on their physicochemical characteristics after being filtered through the glomeruli and released by renal tubules.  Particularly for water-soluble medications and their metabolites, renal excretion is crucial.
• Biliary/Fecal: Drugs or their metabolites that are expelled into bile pass through the digestive system and are expelled as feces.  Enterohepatic recirculation is a process by which certain medications are reabsorbed from the intestines, extending their duration in the body.
• Other Routes: Drugs can also be eliminated through the lungs (e.g., volatile anesthetics), perspiration, saliva, and breast milk, however these routes are less significant quantitatively.  In circumstances of inhaled medications or in particular populations such as nursing mothers, these routes may be therapeutically significant.

Factors Affecting Excretion

A number of factors affect how well drugs are excreted.  In order to prevent toxicity, dose changes may be necessary due to decreased medication clearance caused by compromised renal function.  Weak acids and bases ionize differently depending on urine pH, which impacts their reabsorption and removal.  Drug protein binding can also affect excretion because the kidneys can only filter and secrete a drug's free (unbound) fraction.

Clearance and Elimination Half-Life

A pharmacokinetic measure known as "drug clearance" measures how much plasma a drug is totally eliminated from in a certain amount of time.  It displays the effectiveness of both metabolism and excretion taken together.  The elimination half-life, which is the amount of time needed for a drug's plasma concentration to drop by 50%, is affected by both volume of distribution and clearance.  To ensure therapeutic efficacy, minimize toxicity, and create suitable dosage regimens, knowledge of clearance and half-life is crucial.

Ø  Interrelationship of ADME Processes

The four pharmacokinetic processes—absorption, distribution, metabolism, and excretion—are intricately linked, and modifications to one can have a big impact on the others.  Poor oral drug absorption, for instance, restricts the quantity that enters the systemic circulation and, consequently, the amount that reaches the target tissues.  Since medications may be isolated from excreting organs like the kidneys or metabolizing organs like the liver, extensive distribution into specific tissues can change the rate of metabolism and excretion.  Similar to this, a drug's distribution and excretion might be impacted by changes in metabolism.  Predicting how a medicine will behave in the body and maximizing dosage techniques require an understanding of these interactions.

Concept of Bioavailability

A crucial idea that connects absorption, distribution, and first-pass metabolism to the quantity of active medication that enters the bloodstream is bioavailability.  It is the portion of a given dose that reaches the bloodstream unaltered and in a pharmacologically active state.  Oral medications may have a decreased bioavailability because of partial absorption or substantial first-pass metabolism in the liver, whereas intravenous medications have a 100% bioavailability.  Determining appropriate dosages and comparing various medication formulations or administration methods depend on evaluating bioavailability.

Impact on Therapeutic Efficacy and Toxicity

The therapeutic efficacy and toxicity risk of a medicine are directly impacted by how ADME processes interact.  Adequate distribution and effective absorption guarantee that the target site receives enough medication concentrations to have the intended effect.  Over time, medication levels are regulated by metabolism and excretion, which minimizes side effects and prevents buildup.  Disease, aging, genetic variation, or drug interactions can all cause changes in these pathways that can result in hazardous levels or subtherapeutic effects.  Thus, physicians and pharmaceutical scientists can optimize treatment, attain consistent results, and guarantee patient safety by having a thorough understanding of ADME concepts.

1.2. Historical Evolution of Drug Delivery Technologies

Drug delivery systems have seen a remarkable transformation, progressing from crude techniques of delivering natural chemicals to highly developed systems that can release drugs precisely, precisely, and precisely.  Traditionally, medications were delivered in crude forms, such as herbal extracts, plant resins, and mineral-based mixtures, made into tinctures, poultices, decoctions, or ointments, in ancient civilizations including Egypt, India, China, and Greece.  Pharmacokinetics and pharmacodynamics were not scientifically understood in these early formulations, which instead depended on natural carriers and anecdotal knowledge.  They established the idea of using delivery means to promote treatment outcomes, despite its drawbacks.

 The discovery and isolation of active pharmaceutical ingredients (APIs) transformed medicine in the 19th century as chemistry and pharmaceutical sciences advanced.  In order to provide consistent dosage and enhance patient convenience, this era saw the introduction of traditional dosage forms such tablets, capsules, syrups, and injectable solutions.  The development of formulation science and excipients further enabled regulation of medication absorption and dissolution rates, guaranteeing more consistent therapeutic outcomes.  These early systems' incapacity to sustain steady plasma drug concentrations, which frequently resulted in variations between sub-therapeutic and dangerous levels, was still a drawback.

 Controlled and sustained-release formulations emerged as a result of pharmaceutical research concentrating on addressing the drawbacks of traditional methods around the middle of the 20th century.  Osmotic pumps, matrix systems, and reservoir devices were among the technologies that evolved during this time, allowing for more consistent and longer drug action. These systems were meant to release the medication gradually over a predetermined period, lowering the frequency of dose and improving patient compliance.

Novel drug delivery systems (NDDS) emerged in the late 20th century, bringing about a paradigm shift.  Drugs can now be continuously and non-invasively given through the skin thanks to the use of transdermal patches.  Concurrently, advances in polymeric science produced biodegradable polymers that enhanced drug stability and offered continuous release without requiring the delivery device to be removed.  The field was further improved by the introduction of liposomes, microspheres, and nanoparticles, which allowed medications to be encapsulated to prevent degradation and enable targeted administration to particular tissues or cells.

 Drug delivery is now an interdisciplinary field that combines materials science, biotechnology, and nanotechnology due to the rapid advancement of technology in the twenty-first century.  The creation of intelligent drug delivery systems that can react to pH, temperature, enzymes, or magnetic fields has made it possible for medicinal drugs to be released on-demand and at precise sites.  Furthermore, the way medications are supplied is being redefined by 3D-printed drug formulations, gene delivery vectors, and microneedles, which provide individualized, effective, and minimally invasive substitutes for conventional techniques.

 All things considered, the development of drug delivery systems over time shows a persistent and resolveable attempt by researchers to increase patient adherence, decrease side effects, and improve therapeutic precision.  From the application of unrefined herbal blends to the development of sophisticated, nanoscale technologies, the area keeps developing in the direction of universal access to safe, efficient, and customized healthcare.

1.3.Importance of Delivery Route in Therapeutic Outcomes

Potency and chemical characteristics alone do not determine a drug's effectiveness; the method of administration is just as important.  The speed and effectiveness with which a drug enters the body, how long it stays active in the body, and the possibility of toxicity or adverse effects are all influenced by the routes by which it is administered.  In addition to improving patient safety and compliance, choosing the right route guarantees the best possible therapeutic results.  Pharmaceutical sciences advancements over time have increased the number of administration alternatives available, providing customized solutions for various medication types, clinical situations, and patient requirements.  Designing efficient medication delivery systems thus requires a thorough understanding of the traits, benefits, and drawbacks of each route.

Ø  Importance of Drug Administration Routes

The pharmacokinetic and pharmacodynamic profile of a drug is largely determined by the route of administration, which has a direct impact on how the drug is absorbed, distributed, metabolized, and eliminated by the body.  It affects the duration of the drug's activity, the strength of the therapeutic effect, the commencement of action, and the final clinical result.  A poorly selected route may result in delayed therapeutic results, an increased risk of unpleasant responses, or suboptimal drug levels at the target site.  On the other hand, a suitable route of administration guarantees that the medication effectively reaches its target site of action, sustains therapeutic concentrations for the required amount of time, and reduces toxicity.  In addition to pharmacological factors, route selection affects patient comfort, adherence, and convenience, making it a crucial factor in clinical practice and medication formulation.  To maximize therapeutic efficacy and safety, a number of aspects need to be taken into account, including the drug's physicochemical characteristics, the ailment being treated, the target tissue, and patient-specific factors.

Ø  Classification of Routes of Administration

In general, there are three main types of drug administration routes: topical (or local), parenteral, and enteral.  The unique drug delivery processes, benefits, and drawbacks of each of these routes have a substantial impact on how a medication is absorbed, distributed, metabolized, and eventually produces its therapeutic effect.  The simplicity and non-invasiveness of enteral methods—oral, sublingual, and rectal administration—make them popular. These routes depend on absorption through the gastrointestinal system.  In order to provide rapid onset and total bioavailability—a crucial feature for emergency therapies or medications that are poorly absorbed orally—parenteral methods, such as intravenous, intramuscular, and subcutaneous injections, completely circumvent the gastrointestinal tract.  Lastly, local and topical routes, such as transdermal, ocular, nasal, and pulmonary administration, frequently escape first-pass metabolism and enable either localized drug action or slow systemic absorption.  It is crucial to comprehend the features, advantages, and limitations of different routes of administration in order to develop efficient drug delivery plans, maximize therapeutic results, and improve patient safety and compliance.

Ø  Enteral Routes

Drug absorption via the gastrointestinal (GI) tract is known as an enteral route.  Oral, sublingual, and rectal administration fall within this group.  Because of its excellent patient compliance, non-invasiveness, and simplicity, the oral route is the most widely employed.  Orally administered medications must be able to tolerate the stomach's acidic environment and digestive enzymes. Additionally, they may undergo first-pass metabolism in the liver, which can lower their bioavailability.  Sublingual administration, which involves placing a medication beneath the tongue, offers a quicker beginning of effect by avoiding first-pass metabolism and facilitating quick absorption into the systemic circulation.  When oral consumption is not practical, such as in individuals who are unconscious or vomiting, rectal administration may be helpful.  Although it largely circumvents first-pass metabolism, the state of the rectal mucosa may cause varying absorption.

Ø  Parenteral Routes

Parenteral drug delivery is when pharmaceuticals are administered by pathways that do not pass through the gastrointestinal (GI) tract, allowing them to directly reach the systemic circulation.  The three most widely used parenteral routes—intramuscular (IM), subcutaneous (SC), and intravenous (IV) injections—each have unique properties that are appropriate for certain therapeutic requirements.  An almost instantaneous onset of action and exact control over plasma drug concentrations are made possible by intravenous administration, which puts the medication straight into the bloodstream.  This makes IV administration very useful in critical care settings, emergency scenarios, or when quick therapeutic results are needed.  When IV access is not practical, intramuscular injections are a helpful substitute because the medicine is deposited into muscle tissue and moderately absorbed into the bloodstream. These injections produce effects that are rather long-lasting.  Given into the layer of fat beneath the skin, subcutaneous injections enable slower and more regulated absorption. This makes them ideal for medications that need to have a long-lasting therapeutic effect, like insulin or some vaccinations.

 Parenteral routes have many drawbacks despite their benefits.  They may result in discomfort, bruising, or soreness at the injection site because they are intrusive.  Failure to adhere to aseptic technique can potentially result in infection, tissue irritation, or unintentional harm.  Furthermore, these routes are typically best administered by qualified healthcare professionals, which restricts their suitability for long-term outpatient therapy or self-administration.  Further limiting their use in routine or chronic therapy settings are the expenses and logistical difficulties related to parenteral delivery.  Its vital importance in contemporary pharmacotherapy is highlighted by the fact that parenteral administration is still required for treatments where quick onset, full bioavailability, or exact dosage control are crucial.

Ø  Topical or Local Routes

Topical and local methods may enable systemic absorption through local delivery or target particular tissues.  Transdermal, ocular, nasal, pulmonary, and rectal routes are a few examples.  Transdermal administration offers regulated release and enhanced patient compliance by enabling medications to penetrate the skin and enter the bloodstream over an extended period of time.  Although systemic absorption is limited, ocular injection primarily cures eye disorders locally.  The pulmonary and nasal routes, which avoid first-pass metabolism by using highly vascularized mucosa for quick absorption, are utilized to treat respiratory disorders locally as well as systemically.  These channels hold great promise for inhalation therapy for respiratory illnesses or for delivering medications to the brain through nasal pathways.

 The physicochemical characteristics of the medication, the intended rate and duration of action, the target site, the patient's condition, and convenience are some of the criteria that go into selecting each of these administration methods.  Clinicians and pharmaceutical scientists can maximize treatment, maximize therapeutic efficacy, and limit side effects by having a thorough grasp of these pathways.

1.3.1.     Enteral Routes of Administration

Enteral drug administration, drugs are administered through the gastrointestinal (GI) tract and then absorbed into the bloodstream.  This group comprises the oral, sublingual, and rectal routes; each has unique benefits and drawbacks.  For a variety of treatments, enteral administration is frequently chosen since it is convenient, non-invasive, and easy for patients to comply with.  Physiological obstacles such gastric acidity, digestive enzymes, and liver first-pass metabolism, however, might impact absorption efficiency and limit the bioavailability of medication.  To create formulations that optimize therapeutic efficacy while reducing side effects, it is crucial to comprehend the features, workings, and difficulties of each enteral route.

Ø  Oral Administration

Oral administration is the most widely used route for drug delivery, mainly because of its great patient compliance, non-invasiveness, and ease.  Oral drugs are perfect for long-term treatments because patients can easily self-administer them without a doctor's supervision.  However, before entering the systemic circulation, oral medications must pass through a number of physiological and biochemical obstacles.  Certain medications may become ineffective due to degradation or inactivation caused by the stomach's acidic environment and digestive enzymes.  Furthermore, medications taken orally undergo first-pass metabolism in the liver, which reduces bioavailability by metabolizing a portion of the drug before it enters the bloodstream.  Pharmaceutical experts have created a number of formulation techniques to solve these issues.  Enteric coatings release medications into the more neutral environment of the intestine, preventing them from degrading in the stomach's acidic environment.  Sustained-release formulations lower the frequency of doses while preserving therapeutic plasma levels by releasing the medication gradually over time.  By increasing solubility, stability, and absorption efficiency, nanoparticle encapsulation and other cutting-edge drug delivery methods might improve overall therapeutic results.

Ø  Sublingual Administration

Sublingual administration entails putting a medication beneath the tongue, where it is immediately absorbed through the thin, highly vascularized oral mucosa and into the systemic circulation.  The medicine can enter the systemic circulation quickly by this route, skipping the gastrointestinal tract and liver's first-pass metabolism, which leads to a quick commencement of therapeutic activity.  This feature makes sublingual distribution especially useful for pharmaceuticals that are unstable or poorly absorbed in the gastrointestinal environment, or for therapies that require quick action, such nitroglycerin for the treatment of angina pectoris.

 Sublingual delivery has practical advantages in addition to pharmacokinetic ones.  It is appropriate for people who have trouble swallowing traditional tablets or capsules, such as elderly patients, children, or those with gastrointestinal issues, because it is non-invasive, painless, and generally simple for patients to self-administer.  Additionally, sublingual formulations offer flexibility in dosage and delivery since they can be made as tablets, films, or sprays.  Despite these benefits, the mucosal surface can only effectively absorb relatively small amounts, hence the sublingual route is usually restricted to strong medications needed in small doses.  All things considered, sublingual administration offers a practical and efficient substitute for quick systemic delivery of particular medications, fusing patient-friendliness with pharmacological effectiveness.

Ø  Rectal Administration

Rectal administration gives individuals who are unable to take oral drugs because to severe gastrointestinal problems, vomiting, or unconsciousness an alternate route.  The most popular rectal formulations are enemas or suppositories.  Because part of the rectal venous drainage enters the systemic circulation directly, drugs delivered rectally can partially avoid first-pass metabolism.  However, depending on variables like the delivery site, rectal content, and local blood flow, rectal absorption might be irregular and unpredictable.  Notwithstanding these drawbacks, rectal administration is still a useful choice for systemic medication delivery in individuals with restricted oral intake or for localized treatment.

1.3.2.      Parenteral Routes of Administration

Parenteral drug administration entails avoiding the gastrointestinal tract and delivering drugs straight into the tissues or systemic circulation.  Subcutaneous (SC), intramuscular (IM), and intravenous (IV) injections are the most often used parenteral methods.  These methods guarantee quick beginning of action and full bioavailability by skipping the GI tract's barriers and the liver's first-pass metabolism. This makes them especially useful in critical care, emergency settings, and treatments that call for exact control of plasma drug concentrations.  While intramuscular and subcutaneous routes allow delayed absorption but can still produce predictable systemic effects, intravenous treatment delivers the drug straight into the bloodstream, producing instant pharmacological effects.

 Parenteral approaches have significant drawbacks in lieu of their benefits.  They are intrusive, frequently result in pain or discomfort at the injection site, and, if aseptic procedures are not correctly followed, carry an infection risk.  Furthermore, they typically need to be provided by qualified medical professionals, which limits their applicability for long-term or self-administered therapy and decreases convenience.  As a result, non-invasive delivery methods are chosen for patient-managed care and continuous therapy, while parenteral delivery is typically saved for acute treatment scenarios, medications that are poorly absorbed orally, or circumstances needing precise dose management.

Ø  Topical and Localized Delivery

Topical and localized drug delivery routes allow for gradual systemic absorption through particular body surfaces or deliver medications directly to the site of action, providing targeted therapy.  These modes of administration—transdermal, pulmonary, nasal, and ocular—each have special benefits with regard to bioavailability, duration, and onset.  Many of these techniques avoid first-pass metabolism, in contrast to oral delivery, which enables more consistent systemic exposure and quicker therapeutic benefits.  They also offer less invasive or non-invasive options, which enhance patient comfort and compliance.  To effectively design drug delivery systems that are suited to the patient's therapeutic needs and physiological characteristics, it is imperative to comprehend the mechanisms, advantages, and limitations of various routes.

Ø  Transdermal Delivery

Transdermal drug delivery entails administering medications through the skin so that they can progressively enter the bloodstream over time.  Transdermal patches, gels, or lotions are frequently used to accomplish this method because they offer regulated and prolonged medication delivery.  Transdermal methods reduce oral dosage peaks and troughs by preserving constant plasma drug concentrations, which enhances therapeutic results and patient compliance.  Transdermal delivery can only be used for medications that are sufficiently strong, lipophilic, and able to penetrate the epidermal barrier.  Therapeutic levels may not be reached by this method for drugs that are too big, hydrophilic, or need high dosages.  Despite these drawbacks, transdermal administration is frequently utilized for long-term ailments like pain relief, hormone replacement therapy, and nicotine replacement.

Ø  Pulmonary and Nasal Routes

The pulmonary and nasal routes quickly absorb drugs by taking advantage of the nasal cavity's and lungs' highly vascularized mucosal surfaces.  With pulmonary inhalation, medication is delivered directly to the lungs, where it is most required, and is especially useful for respiratory conditions including asthma and chronic obstructive pulmonary disease (COPD).  The blood-brain barrier is circumvented by nasal administration, which offers a special route for systemic absorption and potentially direct brain targeting.  Both pathways have the benefit of avoiding the liver's first-pass metabolism, which increases the systemic bioavailability of peptides, small compounds, and certain vaccinations.  These pathways are also appropriate for both local and systemic therapeutic applications because to their quick beginning of action.

Ø  Ocular Administration

Ocular drug delivery primarily addresses localized eye disorders such inflammation, infections, or glaucoma.  Formulations that are frequently utilized include eye drops, ointments, and gels.  High local concentrations can be achieved at the site of action by this pathway, but systemic absorption is usually modest because of the nasolacrimal duct drainage, limited corneal permeability, and rapid tear turnover.  Even with its confined focus, ocular administration is essential for treating conditions that need to be precisely targeted to the tissues of the eyes without causing substantial systemic exposure.

1.4.  Classification of Drug Delivery Systems

Drug delivery systems can be categorized from a variety of angles, including the drug's release pattern, the administration route, and the technology or mechanism used.  Every classification offers information about how the formulation is made to maximize therapeutic effectiveness, reduce adverse effects, and enhance patient compliance.

 The most basic classification is based on the drug's release pattern.  Drugs designed for traditional or conventional delivery systems are made to release their active ingredients right after they are administered.  With the help of these immediate-release dosage forms, which include tablets, capsules, syrups, and injectables, the medication can enter the bloodstream quickly and start working.  However, the drug's plasma concentration frequently varies, potentially producing troughs (which could result in sub-therapeutic effects) and peaks (which could produce side effects).

Modified-release systems, which are intended to release the medication in a controlled, prolonged, or delayed manner, were created in order to get around these restrictions.

• Sustained-release formulations release the medication gradually over time, keeping the plasma concentration constant for extended periods of time.
• Controlled-release systems carefully control the drug's release rate and duration to provide a longer therapeutic effect with fewer doses.
• Delayed-release systems, enteric-coated tablets delay the release of the medication until the formulation reaches a particular area of the gastrointestinal tract, reducing gastric discomfort or shielding the medication from deterioration.

The method of administration—oral, parenteral (injectable), transdermal, inhalational, nasal, ophthalmic, rectal, and implanted systems—is another important classification.  Every route has different physiological difficulties and calls for different formulation techniques.  For instance, transdermal systems need to make it easier for drugs to pass through the skin barrier, while oral systems need to be able to endure severe gastrointestinal conditions.  The significance of choosing a suitable delivery method during drug development is highlighted by the direct effects that route selection has on therapeutic performance, patient comfort, and drug bioavailability.

 Novel Drug Delivery Systems (NDDS) are a more contemporary and technologically sophisticated classification that combines concepts from biotechnology, polymer science, and nanotechnology to provide targeted, regulated, and effective delivery.  These systems are designed to improve drug solubility, stability, and site-specific localization in order to get around the drawbacks of traditional dosage forms. Examples include:

• Nanoparticles, which allow penetration across biological barriers and have a large surface area.
• Liposomes, which are phospholipid vesicles that can encapsulate medications that are both lipophilic and hydrophilic while preventing their breakdown.
• Dendrimers, which are tree-like macromolecules with many branches that enable precise drug attachment and release control.
• Hydrogels, which are networks of polymers that, depending on physiological conditions, can swell in water and discharge in a sustained, responsive manner.
• Polymeric carriers and microspheres, created to offer regulated distribution, particularly in injectable depots or implants.

These cutting-edge systems have revolutionized contemporary therapies and opened the door for precision and individualized care.  NDDS maximizes efficacy while minimizing systemic toxicity by facilitating site-specific targeting, which is especially useful in the treatment of complicated and chronic diseases such diabetes, cancer, cardiovascular disease, and neurological disorders.

 Overall, the way drug delivery systems are categorized shows how pharmaceutical science has advanced from straightforward, quick-acting formulations to sophisticated, intelligent platforms that can adjust to biological conditions.  Comprehending these categories aids researchers and medical professionals in creating medication therapies that optimize patient convenience, safety, and efficacy.

1.5.  Overview of Challenges in Conventional Dosage Forms

Conventional dosage forms, including tablets, capsules, syrups, and injections, are widely used and easily accessible, but they have a number of intrinsic drawbacks that may affect the reliability and efficacy of therapeutic results.  Typically, these dosage forms are made for rapid or immediate drug release, which enables a rapid commencement of action but prevents stable and sustained plasma drug concentrations.  Patients may thus experience varying drug levels, with peaks that may approach or surpass dangerous thresholds, raising the possibility of side effects, and periods of sub-therapeutic concentrations that are insufficient to produce the intended pharmacological effect.

 Additionally, the efficiency of drugs can be diminished by physiological and biochemical factors that frequently affect conventional dosage forms.  For instance, oral formulations need to withstand the harsh, acidic environment of the stomach and not be broken down by digestive enzymes.  Additionally, they may undergo first-pass metabolism in the liver, which further lowers bioavailability by metabolizing a sizable amount of the active ingredient before it enters the bloodstream.  Because of their quick clearance or distribution into non-target organs, even parenteral injections, which avoid first-pass metabolism, may nevertheless need regular dosage.

 One additional problem with traditional dose forms is patient compliance.  The effectiveness of treatment can be compromised by missing doses or early medication cessation brought on by frequent dosage schedules, injection discomfort, or gastrointestinal side effects.  Furthermore, traditional systems frequently fail to focus medications to certain tissues or cells, which can lead to systemic adverse effects, decreased therapeutic efficacy, and needless exposure of non-target organs to potentially harmful medications.

These restrictions draw attention to the necessity of sophisticated medication delivery methods that can get around the drawbacks of traditional formulations.  The goals of contemporary delivery systems are to minimize side effects, improve bioavailability, decrease dosage frequency, and provide regulated, sustained, and site-specific drug release.  These cutting-edge solutions improve patient outcomes and adherence by increasing the predictability of drug action and maximizing therapeutic windows, providing a more efficient and patient-friendly method of pharmacotherapy.

 Poor bioavailability is one of the biggest drawbacks of traditional dose forms, especially for medications with high first-pass metabolism, low solubility, or chemical instability.  Many medications that are taken orally experience metabolic breakdown in the liver or gastrointestinal tract before entering the bloodstream, which significantly lowers the quantity of active medication that can be used therapeutically.  Because of this, greater or more frequent dosages are required, which raises the risk of side effects and decreases patient adherence to the prescribed course of therapy.

 REFERENCES

1.     Adepu, S., & Ramakrishna, S. (2021). Controlled drug delivery systems: current status and future directions. Molecules, 26(19), 5905.

2.     Beloqui, A., Solinís, M. Á., Rodríguez-Gascón, A., Almeida, A. J., & Préat, V. (2016). Nanostructured lipid carriers: Promising drug delivery systems for future clinics. Nanomedicine: Nanotechnology, biology and medicine, 12(1), 143-161.

3.     Bharti, C., Nagaich, U., Pal, A. K., & Gulati, N. (2015). Mesoporous silica nanoparticles in target drug delivery system: A review. International journal of pharmaceutical investigation, 5(3), 124.

4.     Chandrakala, V., Aruna, V., & Angajala, G. (2022). Review on metal nanoparticles as nanocarriers: Current challenges and perspectives in drug delivery systems. Emergent Materials, 5(6), 1593-1615.

5.     Dhanasekaran, H. R., Sharma, C. P., & Haridoss, P. (2018). Drug delivery nanosystems—An introduction. Drug Delivery Nanosystems for Biomedical Applications, 1-12.

6.     Din, F. U., Aman, W., Ullah, I., Qureshi, O. S., Mustapha, O., Shafique, S., & Zeb, A. (2017). Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. International journal of nanomedicine, 7291-7309.

7.     Goole, J., & Amighi, K. (2016). 3D printing in pharmaceutics: A new tool for designing customized drug delivery systems. International journal of pharmaceutics, 499(1-2), 376-394.

8.     Guimarães, D., Cavaco-Paulo, A., & Nogueira, E. (2021). Design of liposomes as drug delivery system for therapeutic applications. International journal of pharmaceutics, 601, 120571.

9.     Homayun, B., Lin, X., & Choi, H. J. (2019). Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics, 11(3), 129.

10.  Jain, K. K. (2019). An overview of drug delivery systems. Drug delivery systems, 1-54.

11.  Kumari, P., Ghosh, B., & Biswas, S. (2016). Nanocarriers for cancer-targeted drug delivery. Journal of drug targeting, 24(3), 179-191.

12.  Li, C., Wang, J., Wang, Y., Gao, H., Wei, G., Huang, Y., ... & Jin, Y. (2019). Recent progress in drug delivery. Acta pharmaceutica sinica B, 9(6), 1145-1162.

13.  Li, J., Wang, X., Zhang, T., Wang, C., Huang, Z., Luo, X., & Deng, Y. (2015). A review on phospholipids and their main applications in drug delivery systems. Asian journal of pharmaceutical sciences, 10(2), 81-98.

14.  Liu, D., Yang, F., Xiong, F., & Gu, N. (2016). The smart drug delivery system and its clinical potential. Theranostics, 6(9), 1306.

15.  Liu, P., Chen, G., & Zhang, J. (2022). A review of liposomes as a drug delivery system: current status of approved products, regulatory environments, and future perspectives. Molecules, 27(4), 1372.